Co-morbidity in general practice.
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Acute Disease↗
Biomedical subjects
K Chan
Publications and source records attributed to K Chan.
Large multi-chromosomal duplications encompass many members of the olfactory receptor gene family in the human genome.
The human genome contains thousands of genes that encode a diverse repertoire of odorant receptors (ORs). We report here on the identification and chromosomal localization of 74 OR-containing genomic clones. Using fluorescence in situ hybridization (FISH), we demonstrate a striking homology among a set of approximately 20 OR locations, illustrating a history of duplications that have distributed OR sequences across the genome. Half of the OR-containing BACs cloned from total genomic DNA and 86% of cosmids derived from chromosome 3 cross-hybridize to a subset of these locations, many to 17 of them. These paralogous regions are distributed on 13 chromosomes, and eight lie in terminal bands. By analyzing clones from an approximately 250 kb clone-walk across one of these sites (3p13), we show that the homology among these sites is extensive (>150 kb) and encompasses both OR genes and intergenic genomic sequences. The FISH signals appear significantly larger at some sites than at the native location, indicating that portions of some duplicons have undergone local amplification/attrition. More restricted duplications involving pairs of other genomic locations are detected with 12% of the OR-BACs. Only a small subset of OR locations is sufficiently diverged from the others that clones derived from them behave as single-copy FISH probes. We estimate that duplications encompassing members of the OR gene family account for >0.1% of the human genome. A comparison of FISH signals at orthologous locations in other primates indicates that a portion of this OR 'subgenome' has been in flux during the divergence of primates, possibly as a mechanism for evolving the repertoire of olfactory receptors.
Animals↗
Spontaneous bruising in an elderly woman.
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Aged↗
Megakaryocytes endocytose insulin-like growth factor (IGF) I and IGF-binding protein-3: a novel mechanism directing them into alpha granules of platelets.
Lysis of platelets releases the contents of the alpha-granules, which contain growth factors, including insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3). We investigated the mechanism by which IGF-I and IGFBP-3 appeared in the alpha-granules with a goal of modulating their levels in platelets to affect platelet functions. Reverse transcription-PCR was initially used to test whether megakaryocytes contained IGFBP-3 and IGF-I messenger RNA transcripts. We found that megakaryocytes did not express the IGFBP-3 gene, but did have IGF-I messenger RNA. We subsequently investigated whether they incorporated IGFBP-3 and IGF-I by the process of endocytosis and packaged them into the alpha-granules. This hypothesis was tested in two ways. 1) We examined whether during pregnancy in the rat the alpha-granule content for IGFBP-3 paralleled the changes in plasma IGFBP-3 levels caused by the pregnancy-induced IGFBP-3 protease. The alpha-granule contents of both IGFBP-3 and IGF-I declined in parallel to the plasma changes in pregnant rats and returned to normal postpartum. As the binding protein protease acts extracellularly, endocytosis of the IGF-I:IGFBP-3 complex from the extracellular fluid by megakaryocytes was suggested. 2) We tested whether an IGF-I:IGFBP-3 complex comprised of human IGF-I and IGFBP-3 (recombinant 28.7 kDa) injected i.v. appeared in rat platelet alpha-granules. Hypophysectomized rats were injected i.v. with 5.24 mg of a 1:1 complex of IGF-I:IGFBP-3. After 24 h, platelet lysates were prepared and analyzed for IGFBP-3 by Western ligand blotting, and IGF-I was determined by RIA. Platelet lysates of the treated animals showed a prominent new band at approximately 28 kDa, whereas control rats were negative. In addition, the alpha-granule IGF-I concentration increased from 0.38 to 1.9 ng/1 x 10(9) platelets. These results indicate that the IGF-I:IGFBP-3 complex is taken up by megakaryocytes and packaged into the alpha-granules of platelets and demonstrate how the contents of IGF-I and IGFBP-3 in platelets can be modulated by their plasma concentrations. As reverse transcription-PCR has shown that the IGF-I, but not the IGFBP-3, gene is expressed by megakaryocytes, there may be two mechanisms for directing IGF-I into the alpha-granules of platelets.
Animals↗
Depression, health-related quality of life, and medical cost outcomes of receiving recommended levels of antidepressant treatment.
BACKGROUND: We evaluated depression severity, health-related quality of life (HRQL), and medical cost outcomes of primary care patients receiving recommended and less-than-recommended levels of antidepressant treatment. METHODS: We performed a secondary analysis of clinical trial data from primary care clinics in a staff-model managed care organization. The trial included patients with Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R) criteria for major depression who were starting antidepressant treatment. The primary outcomes measures used were the 17-item Hamilton Depression Rating Scale (HDRS), Hopkins Symptom Checklist depression scores, the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) mental and physical component summary scores, and the total outpatient and inpatient medical costs. RESULTS: Of 358 patients starting antidepressant treatment, 195 (54.5%) received doses recommended by the Agency for Health Care Policy and Research for 90 days or more. Mean HDRS score decreased from 14.1 to 8.8 in patients receiving less-than-recommended treatment and decreased from 13.8 to 8.9 in patients with minimum recommended treatment (P = .761). No significant differences in improvement of HRQL outcomes during 6 months were observed between patients receiving recommended or less-than-recommended antidepressant therapy. Mean total medical costs over 6 months for patients taking the recommended levels of antidepressant treatment were $1872 +/- 140 compared with $2622 +/- 413 for patients taking less-than-recommended treatment (P = .032). The differences in total medical costs were attributable to significantly lower nonmental health-related inpatient costs in the recommended antidepressant treatment group ($104 vs $785, P = .004). CONCLUSIONS: Patients receiving minimum recommended levels of antidepressant therapy for 3 months showed improvement in depression severity and HRQL comparable with patients receiving less-than-recommended treatment. Patients receiving minimum recommended treatment had lower total costs and nonmental health-related inpatient costs. Antidepressant treatment in primary care patients may have the greatest impact on the frequency of health care visits and on costs for medical conditions and impairments.
Adult↗
Clinical opinions on transfusion triggers.
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Algorithms↗
Potent alpha 4 beta 1 peptide antagonists as potential anti-inflammatory agents.
The migration, adhesion, and subsequent extravasation of leukocytes into inflamed tissues contribute to the pathogenesis of a variety of inflammatory diseases including asthma, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. The integrin adhesion receptor alpha 4 beta 1 expressed on leukocytes binds to the extracellular matrix protein fibronectin and to the cytokine inducible vascular cell adhesion molecule-1 (VCAM-1) at inflamed sites. Binding of alpha 4 beta 1 to VCAM-1 initiates firm adhesion of the leukocyte to the vascular endothelium followed by extravasation into the tissue. Monoclonal antibodies generated against either alpha 4 beta 1 or VCAM-1 can moderate this inflammatory response in a variety of animal models. Recently peptides containing a consensus LDV sequence based on the connecting segment-1 (CS-1) of fibronectin and cyclic peptides containing an RCD motif have shown promise in modulating leukocyte migration and inflammation presumably by blocking the interaction of alpha 4 beta 1 with VCAM-1. Here we describe novel, highly potent, cyclic peptides that competitively inhibit alpha 4 beta 1 binding to VCAM-1 and fibronectin at sub nanomolar concentrations. The structure of a representative analog was determined via NMR spectroscopy and used to facilitate optimization of peptide leads. The peptides discussed here utilize similar functional groups as the binding epitope of VCAM-1, inhibit lymphocyte migration in vivo, and are highly selective for alpha 4 beta 1. Furthermore the structure--activity relationships described here have provided a template for the structure-based design of small molecule antagonists of alpha 4 beta 1-mediated cell adhesion processes.
Animals↗
hMAF, a small human transcription factor that heterodimerizes specifically with Nrf1 and Nrf2.
A 1.6-kilobase pair full-length cDNA encoding a transcription factor homologous to the Maf family of proteins was isolated by screening a K562 cDNA library with the NFE2 tandem repeat probe derived from the globin locus control region. The protein, which was designated hMAF, contains a basic DNA binding domain and an extended leucine zipper but lacks any recognizable activation domain. Expressed in vitro, the hMAF protein is able to homodimerize in solution and band-shift the NFE2 tandem repeat probe. In addition to homodimers, hMAF can also form high affinity heterodimers with two members of the NFE2/CNC-bZip family (Nrf1 and Nrf2) but not with a third family member, p45-NFE2. Although hMAF/hMAF homodimers and hMAF/Nrf1 and hMAF/Nrf2 heterodimers bind to the same NFE2 site, they exert functionally opposite effects on the activity of a linked gamma-globin gene. In fact, whereas all hMAF/CNC-bZip heterodimers stimulate the activity of a gamma-promoter reporter construct in K562 cells, the association into homodimers that is induced by overexpressing hMAF inhibits the activity of the same construct. Thus variations in the expression of hMAF may account for the modulation in the activity of the genes that bear NFE2 recognition sites.
Amino Acid Sequence↗
Simultaneous determination of imipramine, desipramine and their 2- and 10-hydroxylated metabolites in human plasma and urine by high-performance liquid chromatography.
A simultaneous assay for imipramine, desipramine and their 2- and 10-hydroxy-metabolites using high-performance liquid chromatography (HPLC) is described. The drugs and internal standard, pericyazine, were extracted from plasma or urine at pH 9.6 with diethyl ether and back-extracted into 0.1 M orthophosphoric acid. The recovery of the compounds ranged from 78.6% for imipramine to 94.3% for 2-hydroxydesipramine. The extracts were analysed by reversed-phase HPLC with electrochemical detection using a mobile phase of 30% acetonitrile in 0.1 M K2HPO4 at pH 6.0 delivered at 2 ml/min. All compounds were resolved in a run time of 15 min with lower limits of quantification of 1.5 ng/ml for hydroxy-metabolites and 3 ng/ml for imipramine and desipramine. The intra- and inter-day coefficients of variation at 50 ng/ml were 5.2% and 6.8%, respectively (n=8).
Adult↗
A new technique for performing Syed-Neblett template interstitial implants for gynecologic malignancies using transrectal-ultrasound guidance.
PURPOSE: Interstitial brachytherapy plays an important role in the treatment of advanced and recurrent gynecologic malignancies. Unfortunately, the inability to visualize the tumor and surrounding normal structures during the implant has hampered the accuracy and safety of the implant. Transrectal ultrasound guided Syed-Neblett template implantation is a new technique for performing interstitial implants under direct visualization. The details of the technique are presented to demonstrate the ability to accurately guide needle placement into tumor and avoid needle insertion into critical surrounding normal structures. METHODS AND MATERIALS: The transrectal ultrasound is positioned so that it can visualize the tumor, and normal surrounding structures in both transverse and longitudinal planes. The Syed-Neblett template is positioned and sutured into the perineum. Needles are inserted into the target area under direct visualization through transverse imaging. The bladder and rectum can be directly imaged and thus avoided. Longitudinal imaging is then used to guide the needles to the appropriate depth. In addition, it can be used to assess the length of the target volume and aid in determining the active length of the sources. RESULTS: A total of 12 procedures have been performed on seven patients from August 30, 1995 to April 12, 1996. The presenting diseases included: Stage IIIb cervical cancer in four cases, recurrent endometrial cancer in two cases, and Stage III vaginal cancer in one case. The total length of time for implantation of the needles ranged from 45 to 165 min (median--130 min). CONCLUSION: Transrectal ultrasound guidance provides real-time visualization of the target volume and normal tissues during interstitial implantation of gynecologic malignancies and allows for accurate needle placement.
Aged↗
General aspects of insulin-like growth factor binding proteins.
Insulin-like growth factor binding proteins (IGFBPs) belong to a family of at least six homologous proteins that bind insulin-like growth factors (IGFs) and modulate many of their biological actions. IGFBPs are produced by a wide variety of tissues and their circulating levels are regulated by both hormonal and metabolic factors. The binding activity of some IGFBPs is affected by phosphorylation, proteolysis, or association with extracellular matric (ECM) and plasma membrane. The IGFBPs may exert either inhibitory or potentiating effects on IGF actions. Recent evidence indicate that some IGFBPs are capable of direct actions on cells independent of the IGFs.
Aging↗
2,6-di-tert-butylphenols: a new class of potent and selective PGHS-2 inhibitor.
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Cyclooxygenase Inhibitors↗
Ovine fetal laryngeal chemoreflex thresholds and respiratory effects.
In newborn infants, laryngeal contact with solutions of low chloride concentration or pH evokes swallowing, laryngeal adduction, and respiratory inhibition (laryngeal chemoreflex). To determine whether the laryngeal chemoreflex is present during fetal life and its effect on fetal respiratory activity, eight time-bred ewes (128 +/- 2 days) were prepared with fetal electrocortical diaphragm and esophageal electrodes and a nasopharyngeal catheter. After a 60-minute control period, increasing volumes (0.1 to 1.0 ml/kg) of 0.15 mol/L NaCl or distilled water (0.05 to 1.0 ml/kg) and decreasing concentrations of NaCl (0.15 to 0.02 mol/L) at a fixed volume (0.3 ml/kg) were sequentially administered through the nasopharyngeal catheter (38 degrees C). The minimum water volume that stimulated swallowing was significantly less than the minimum 0.15 mol/L NaCl volume (0.10 +/- 0.02 vs. 0.70 +/- 0.05 ml/kg). The maximum NaCl concentration that stimulated swallowing was 0.04 +/- 0.01 mol/L During the control period, respiratory activity averaged 14.6 +/- 0.7 breaths/minute and did not change during absent swallow responses or isotonic saline-induced swallows. However, respiratory activity significantly decreased during water (4.7 +/- 0.6 breaths/minute) and hypotonic saline-induced swallow responses (3.7 +/- 0.7 breaths/minute). Fetal electrocortical activity did not change during absent or stimulated swallows. We conclude that laryngeal water or hypotonic saline solution may stimulate fetal swallowing and suppress fetal respiratory activity, similar to the newborn laryngeal chemoreflex. We speculate that an exaggeration of the laryngeal chemoreflex apnea response in the newborn may predispose to sudden infant death syndrome.
Animals↗
Scale-up of adhesive transdermal drug delivery systems.
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Adhesives↗
The mechanisms of enhancement and inhibition of field stimulation responses of guinea-pig vas deferens by prostacyclin analogues.
1. In the guinea-pig isolated vas deferens preparation bathed in Tyrode's solution, the prostacyclin analogues, cicaprost, TEI-9063, iloprost, taprostene and benzodioxane-prostacyclin, enhanced twitch responses to submaximal electrical field stimulation (20%-EFS). The high potency of cicaprost (EC150 = 1.3 nM) and the relative potencies of the analogues (equi-effective molar ratios = 1.0, 0.85, 1.6, 17 and 82, respectively) suggest the involvement of a prostacyclin (IP-) receptor. 2. Maximum enhancement induced by cicaprost in 2.5 mM K+ Krebs-Henseleit solution was similar to that in Tyrode solution (2.7 mM K+), but was progressively reduced as the K+ concentration was increased to 3.9, 5.9 and 11.9 mM. There was also a greater tendency for the other prostacyclin analogues to inhibit EFS responses in 5.9 mM standard K+ Krebs-Henseleit solution; this may be attributed to their agonist actions on presynaptic EP3-receptors resulting in inhibition of transmitter release. 3. The EFS enhancing action of cicaprost was not affected by the alpha1-adrenoceptor antagonist prazosin (100 and 1000 nM). Cicaprost (20 and 200 nM) did not affect contractile responses of the vas deferens to either ATP (5 microM) or alpha,beta-methylene ATP (1 microM) in the presence of tetrodotoxin (TTX, 100 nM). In addition, enhancement by cicaprost of responses to higher concentrations of ATP (30 and 300 microM) in the absence of TTX, as shown previously by others, was not seen. Prostaglandin E2 (PGE2, 10 nM) and another prostacyclin analogue TEI-3356 (20 nM) enhanced purinoceptor agonist responses. Unexpectedly, TTX (0.1 and 1 microM) partially inhibited contractions elicited by 10-1000 microM ATP; contractions elicited by 1-3 microM ATP were unaffected. Further studies are required to establish whether a pre- or post-synaptic mechanism is involved. 4. In a separate series of experiments, cicaprost (5-250 nM), TEI-9063 (3-300 nM), 4-aminopyridine (10-100 microM) and tetraethylammonium (100-1000 microM) enhanced both 20%-EFS responses and the accompanying overflow of noradrenaline to a similar extent. In further experiments with the EP1-receptor antagonist AH 6809, TEI-3356 (1.0-100 nM) and the EP3-receptor agonist, sulprostone (0.1-1.0 nM) inhibited both maximal EFS responses and noradrenaline overflow, thus confirming previous reports of the high activity of TEI-3356 at the EP3-receptor. Cicaprost had no significant effect on noradrenaline overflow at 10 and 100 nM, but produced a modest inhibition at 640 nM. 5. In conclusion, our studies show that prostacyclin analogues (particularly TEI-3356) can inhibit EFS responses of the guinea-pig vas deferens by acting as agonists at presynaptic EP3-receptors. Prostacyclin analogues (particularly cicaprost and TEI-9063) can also enhance EFS responses through activation of IP-receptors. The mechanism of the enhancement has not been rigorously established but from our results we favour a presynaptic action to increase transmitter release.
Adenosine Triphosphate↗
Comparison of cytomegalovirus antigenemia and shell vial culture in allogeneic marrow transplantation recipients receiving ganciclovir prophylaxis.
We prospectively monitored 61 allogeneic BMT patients for evidence of CMV infection and disease starting 7 days prior to transplant until day 110 after transplant. Patients receiving pre- and post-transplantation ganciclovir prophylaxis were followed for the incidence of infection by the CMV antigenemia assay and shell vial cultures. The median age of all patients was 32 years (range 5-54 years). Fourteen (25%) of 57 evaluable patients became CMV antigenemia or culture positive. The incidence of culture or antigenemia positivity in CMV seropositive or seronegative patients with a seropositive donor was 29% (14 of 49 patients). The antigenemia assay became positive a median of 29 days (range 12-89 days) after BMT as compared to 46 days (range 26-98 days) by shell vial assay (P < 0.001). There were no cases of CMV disease in the first 110 days after transplant. This study demonstrates that despite the use of prophylactic ganciclovir, BMT patients developed CMV infection but did not progress to disease in this study, the CMV antigenemia assay may be used to monitor for CMV infection during prophylaxis, and the current regimens for CMV prophylaxis with ganciclovir may require further evaluation to determine an optimal regimen to prevent CMV infection.
Adolescent↗
Lithium pharmacokinetics in Chinese manic-depressive patients.
The pharmacokinetics of lithium was studied in 16 manic-depressive Chinese adults who were on lithium therapy in Hong Kong. A two-compartment open model was used to describe the plasma data obtained. The steady-state volume of distribution and total plasma clearance were estimated to be 63.4 +/- 38.3 L and 1.47 +/- 0.49 L/hr, respectively, which were similar to those reported in studies of Caucasian subjects. The lithium clearance was found to be significantly related to lean body mass (r = 0.646, p < 0.01) but not to either total body weight, age, or creatinine clearance. Interindividual variability in lithium clearance was substantially reduced to a coefficient of variation of 24.6% from 33.3% when lean body mass was considered. The combined plasma and urine data indicate that the rate and extent of lithium absorption were similar to those of earlier studies in Caucasian subjects on a standard lithium dosage.
Adult↗
A new method for bronchial-provocation testing in asthmatic subjects using a dry powder of mannitol.
We developed a bronchial provocation test (BPT) with a dry powder preparation of mannitol. The mannitol was inhaled from gelatin capsules containing 5, 10, 20, or 40 mg to a cumulative dose of 635 mg, and was delivered via an inhalator, Halermatic, or Dinkihaler device. We studied the airway sensitivity to inhaled mannitol, the repeatability of the response, and the recovery after challenge in 43 asthmatic subjects 18 to 39 yr of age who had a 20% decrease in FEV1 in response to inhaling a 4.5% NaCl. We compared this with the airway response to methacholine in 25 subjects. The geometric mean (GM) for the dose of dry mannitol required to reduce the FEV1 by 15% of the baseline value (PD15) was 64 mg, with a 95% confidence interval (CI) of 45 to 91. Subjects responsive to mannitol had a PD20 to metacholine of < 7.8 mumol, with a GM of 0.7 mumol (CI: 0.4 to 1.2). For the first of two challenges to mannitol the PD15 was 59 mg (CI: 36 to 97) and for the second the PD15 was 58 mg (CI: 35 to 94) p = 0.91 (n = 23). Spontaneous recovery to within 5% of baseline occurred within 60 min and within 10 min after 0.5 mg terbutaline sulfate was inhaled. Arterial oxygen saturation (SaO2) remained at 93% or above during mannitol challenge. Subjects tolerated the inhalation of the mannitol well. A dry powder preparation of mannitol may be suitable to develop for bronchial provocation testing.
Administration, Inhalation↗